Dietary Fiber Intake and Risk of Colorectal Cancer - CiteSeerX

ORIGINAL CONTRIBUTION

Dietary Fiber Intake and Risk of Colorectal Cancer A Pooled Analysis of Prospective Cohort Studies Yikyung Park, ScD David J. Hunter, MB, BS Donna Spiegelman, ScD Leif Bergkvist, MD Franco Berrino, MD Piet A. van den Brandt, PhD Julie E. Buring, ScD Graham A. Colditz, MD Jo L. Freudenheim, PhD Charles S. Fuchs, MD Edward Giovannucci, MD R. Alexandra Goldbohm, PhD Saxon Graham, PhD Lisa Harnack, DrPH Anne M. Hartman, MS David R. Jacobs, Jr, PhD Ikuko Kato, MD Vittorio Krogh, MD Michael F. Leitzmann, MD Marjorie L. McCullough, ScD Anthony B. Miller, MB, BCh Pirjo Pietinen, ScD Thomas E. Rohan, MB, BS Arthur Schatzkin, MD Walter C. Willett, MD Alicja Wolk, DMSc Anne Zeleniuch-Jacquotte, MD Shumin M. Zhang, ScD Stephanie A. Smith-Warner, PhD

For editorial comment see p 2904.

Context Inconsistent findings from observational studies have continued the controversy over the effects of dietary fiber on colorectal cancer. Objective To evaluate the association between dietary fiber intake and risk of colorectal cancer. Design, Setting, and Participants From 13 prospective cohort studies included in the Pooling Project of Prospective Studies of Diet and Cancer, 725 628 men and women were followed up for 6 to 20 years across studies. Study- and sex-specific relative risks (RRs) were estimated with the Cox proportional hazards model and were subsequently pooled using a random-effects model. Main Outcome Measure Incident colorectal cancer. Results During 6 to 20 years of follow-up across studies, 8081 colorectal cancer cases were identified. For comparison of the highest vs lowest study- and sex-specific quintile of dietary fiber intake, a significant inverse association was found in the ageadjusted model (pooled RR=0.84; 95% confidence interval [CI], 0.77-0.92). However, the association was attenuated and no longer statistically significant after adjusting for other risk factors (pooled multivariate RR=0.94; 95% CI, 0.86-1.03). In categorical analyses compared with dietary fiber intake of 10 to ⬍15 g/d, the pooled multivariate RR was 1.18 (95% CI, 1.05-1.31) for less than 10 g/d (11% of the overall study population); and RR, 1.00 (95% CI, 0.85-1.17) for 30 or more g/d. Fiber intake from cereals, fruits, and vegetables was not associated with risk of colorectal cancer. The pooled multivariate RRs comparing the highest vs lowest study- and sex-specific quintile of dietary fiber intake were 1.00 (95% CI, 0.90-1.11) for colon cancer and 0.85 (95% CI, 0.72-1.01) for rectal cancer (P for common effects by tumor site=.07). Conclusions In this large pooled analysis, dietary fiber intake was inversely associated with risk of colorectal cancer in age-adjusted analyses. However, after accounting for other dietary risk factors, high dietary fiber intake was not associated with a reduced risk of colorectal cancer. www.jama.com

JAMA. 2005;294:2849-2857

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IETARY FIBER HAS BEEN HYpothesized to reduce the risk of colorectal cancer. Potential mechanisms for a protective effect include dilution of fecal carcinogens and procarcinogens, reduction of transit time of feces through the bowel, production of short chain fatty acids, which promote anticarcinogenic action, and binding of carcinogenic bile acids.1 However, the results

©2005 American Medical Association. All rights reserved.

of numerous epidemiological studies have been inconsistent. Ecological correlation studies and many casecontrol studies have found an inverse association between dietary fiber intake and risk of colorectal cancer.2 On Author Affiliations are listed at the end of this article. Corresponding Author: Stephanie A. Smith-Warner, PhD, Department of Nutrition, Harvard School of Public Health, 665 Huntington Ave, Boston, MA 02115 ([email protected]).

(Reprinted) JAMA, December 14, 2005—Vol 294, No. 22

Downloaded from www.jama.com at University of Maastricht, on May 4, 2006

2849

DIETARY FIBER AND COLORECTAL CANCER RISK

the other hand, most prospective cohort studies have found no association between dietary fiber intake and risk of colorectal cancer3-7 or adenomas (precursors of colorectal cancer),8 and randomized clinical trials of dietary fiber supplementation have failed to show reductions in the recurrence of colorectal adenomas.9-12 Recently, the European Prospective Investigation into Cancer and Nutrition (EPIC) study and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial observed a statistically significant 25% lower risk of colorectal cancer13,14 or adenomas,15 respectively, in the highest quintile of dietary fiber intake compared with the lowest. Because of these discordant results, the debate continues on whether dietary fiber consumption decreases colorectal cancer risk. In this study, we evaluated the association between dietary fiber intake and risk of colorectal cancer by reanalyzing the primary data from 13 prospective cohort studies. METHODS Study Population

The Pooling Project of Prospective Studies of Diet and Cancer (Pooling Project) was established to summarize the association between dietary factors and risk of cancers, and the details of the Pooling Project have been described previously.16 For the colorectal cancer analyses, we identified 13 prospective cohort studies3-6,17-25 that met the following inclusion criteria: (1) at least 50 incident colorectal cancer cases; (2) assessment of usual dietary intake; (3) completion of a validation study of the dietary assessment method or a closely related instrument; and (4) assessment of dietary fiber intake. Studies including men and women6,18,19 were separated into sex-specific cohorts. Dietary and Nondietary Assessment

Each study provided baseline intake data of foods and nutrients that were assessed by a study-specific food frequency questionnaire. We calculated energy-adjusted intakes using the re-

sidual method,26 in which loge transformed intake of each nutrient (excluding energy) was regressed against loge transformed energy intake and then standardized to energy intakes of 2100 kcal/d for men and 1600 kcal/d for women. Pearson correlation coefficients between dietary fiber intake from the food frequency questionnaire and the reference method in the validation studies were higher than 0.50 in all studies.27-36 Grain foods were categorized as either whole grain foods (⬎50% whole grain content) or refined grain foods (ⱕ50% whole grain content).37 We also received information on nondietary risk factors, which was collected by self-administered questionnaires at baseline in each study. Case Ascertainment

Incident colorectal cancer cases were identified by each cohort through selfadministered questionnaires with subsequent medical record review,3,22,25 linkage with a cancer registry,4,17-21 or both.5,6,23,24 Some studies also had an additional linkage with a death registry.3-6,17,19,21-24 The follow-up rate of these studies was generally over 90%. Statistical Analysis

In addition to applying the exclusionary criteria used by each study, we also excluded individuals from the analyses who had a history of cancer other than nonmelanoma skin cancer at baseline and who reported implausible energy intakes (beyond 3 SDs from the study-specific loge-transformed mean energy intake). Data analyses comprised study- and sex-specific analyses and subsequent pooled analyses of the study-specific results. Study- and sex-specific relative risks (RRs) and 2-sided 95% confidence intervals (CIs) were estimated with the Cox proportional hazards model.38 SAS statistical software (version 8, SAS Institute Inc, Cary, NC)39 was used for all studies except the Canadian National Breast Screening Study and the Netherlands Cohort Study, which were analyzed as case-cohort studies40 using Epicure software (ver-

2850 JAMA, December 14, 2005—Vol 294, No. 22 (Reprinted)

sion 2.11, HiroSoft International Corp, Seattle, Wash).41 Age at baseline (in years) and the year when the baseline questionnaire was returned were used as stratification variables, thereby creating a time metric that simultaneously accounted for age, calendar time, and time after entry into the study. Person-years of follow-up time were calculated from the date of the baseline questionnaire until the date of colorectal cancer diagnosis, death, or end of follow-up, whichever came first. The person-time experienced during the follow-up of the Nurses’ Health Study was divided into 2 asymptotically uncorrelated segments42 to take advantage of the more detailed dietary assessment in 1986. The RRs of colorectal cancer were estimated according to study-specific quintiles, as well as to categories defined by absolute intake cut points that were identical across studies. We performed study- and sex-specific ageadjusted and multivariate analyses. The proportion of missing values for each covariate measured in a study was generally less than 5%; an indicator variable for missing responses was created for each covariate in a study if needed. The test for trend across categories of intake was performed by assigning participants the median value of their category and entering those values as a continuous term in a regression model. The pooled estimates and 95% CIs were calculated using a random-effects model that weighted individual studyspecific loge RRs by the inverse of the sum of their variance. Between-studies heterogeneity was tested by the Q statistic.43 Differences in results among tumor sites were tested by the Wald test statistic.44 A meta-regression model was used to test for variation in RRs by sex, geographical location of the study, and follow-up time.45 In addition, we evaluated whether dietary fiber intake was log-linearly associated with risk of colorectal cancer by comparing the nonparametric regression curve obtained using restricted cubic splines with the linear model using the likelihood ratio test and by visual in-




spection of the restricted cubic spline graphs.46 For this analysis, all studies were combined into a single data set stratified by study, and the number and location of the knots were identified through a stepwise selection process. The effect of misclassification of dietary fiber intake was evaluated by the method developed by Zucker and Spiegelman.47 RESULTS During follow-up times of 6 to 20 years in 13 cohort studies, 7 328 414 personyears were accumulated and 8081 incident colorectal cancer cases were identified (2776 men and 5305 women; 5726 colon cancer and 2188 rectal cancer cases plus 167 site unspecified). Among the studies, median energy-adjusted dietary fiber intake ranged from 14 to 28 g/d in men and from 13 to 24 g/d in women. The ma-

jor source of dietary fiber varied across studies with cereals as a major contributor to dietary fiber intake in the European studies, and fruits and vegetables as the main sources in the North American studies (TABLE 1). In the age-adjusted model, dietary fiber intake was significantly associated with a 16% lower risk of colorectal cancer in the highest quintile compared with the lowest (pooled age-adjusted RR=0.84; 95% CI, 0.77-0.92) (TABLE 2). This association was attenuated slightly but still remained statistically significant after adjusting for nondietary risk factors, multivitamin use, and total energy intake (multivariate model I). Additional adjustment for dietary folate intake further weakened the association (multivariate model II). In the final model, which further adjusted for red meat, total milk, and alcohol intake, only a nonsignificant weak inverse associa-

tion was found (pooled RR=0.94; 95% CI, 0.86-1.03; P for trend=.75; multivariate model III). There was no statistically significant heterogeneity between studies for the highest quintile indicating that the differences in the study-specific results were compatible with random variation (FIGURE 1). When we combined the studies into a single data set and analyzed associations using across-study sex-specific quintiles and adjusted for the same covariates in multivariate model III, the results were similar: compared with the lowest quintile (mean intake=11 g/d in men and 10 g/d in women), for quintile 2 (multivariate RR, 0.91; 95% CI, 0.84-0.99); for quintile 3 (multivariate RR, 0.98; 95% CI, 0.89-1.07); for quintile 4 (multivariate RR, 0.95; 95% CI, 0.86-1.04); and for quintile 5 (multivariate RR, 0.95; 95% CI, 0.86-1.06, mean intake=31 g/d in men and 25 g/d

Table 1. Description of Studies in the Analyses of Dietary Fiber and Colorectal Cancer in the Pooling Project

Study Men Alpha-Tocopherol Beta-Carotene Cancer Prevention Study (ATBC) Cancer Prevention Study II Nutrition Cohort (CPS2) Health Professionals Follow-Up Study (HPFS) Netherlands Cohort Study (NLCS) New York State Cohort (NYSC) Women Breast Cancer Detection Demonstration Project Follow-up Study (BCDDP) Canadian National Breast Screening Study (CNBSS) Cancer Prevention Study II Nutrition Cohort (CPS2) Iowa Women’s Health Study (IWHS) Netherlands Cohort Study (NLCS) New York State Cohort (NYSC) New York University Women’s Health Study (NYUWHS) Nurses’ Health Study (a) (NHSa) Nurses’ Health Study (b) (NHSb)† Prospective Study on Hormones, Diet, and Breast Cancer (ORDET) Swedish Mammography Cohort (SMC) Women’s Health Study (WHS) Total

Median (10th−90th Percentile) Fiber Intake From, g/d

Follow-up Time

Baseline Cohort, No.

Colorectal Cancer Cases, No.

1985-1999

26 987

321

19 (13-27)

12 (7-20)

2 (1-4)

4 (2-6)

1992-1999

66 090

720

14 (9-22)

5 (3-9)

3 (1-6)

5 (3-9)

1986-2000

47 766

597

21 (14-31)

5 (3-11)

4 (1-9)

7 (4-12)

1986-1993 1980-1987

58 279 30 363

646 492

27 (20-38) 28 (20-39)

11 (6-19) 6 (5-7)

3 (1-6) 6 (2-12)

4 (2-7) 14 (9-22)

1987-1998

41 987

436

13 (8-21)

5 (2-9)

3 (1-7)

3 (2-6)

1980-2000

49 613

612

16 (10-24)

3 (2-5)

6 (4-11)

3 (1-7)

1992-1999

74 053

479

13 (8-19)

4 (2-8)

3 (1-6)

4 (2-8)

1986-2001 1986-1993 1980-1987 1985-1998

34 588 62 573 22 550 13 258

1010 501 296 127

18 (12-26) 24 (18-32) 24 (17-33) 14 (8-22)

4 (2-8) 9 (5-15) 5 (4-6) 3 (2-7)

4 (2-8) 4 (2-7) 5 (2-10) 4 (1-8)

7 (4-11) 4 (2-7) 11 (7-18) 5 (2-10)

1980-1986 1986-2000 1989-2001

88 651 68 502 9027

220 648 61

13 (8-20) 17 (12-24) 18 (13-23)

2 (1-4) 4 (2-7) 8 (5-11)

4 (1-8) 4 (1-8) 5 (2-9)

4 (2-8) 6 (3-10) 3 (2-6)

1987-2003 1993-2002

61 459 38 384 725 628

714 201 8081

20 (14-27) 17 (12-25)

13 (7-19) 4 (2-6)

3 (1-7) 3 (1-7)

1 (1-3) 6 (3-10)

Dietary Fiber Intake, g/d*

Cereals

Fruits

Vegetables

*Median and 10th-90th percentile intake. †The NHSb is a subset of the NHSa and is not included in the total baseline cohort.




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Table 2. Pooled Relative Risks of Colorectal Cancer for Quintiles of Dietary Fiber Intake

Quintile*

Colorectal cancer (n = 8081) Age-adjusted Multivariate I‡ Multivariate II§ Multivariate III 㛳 Colon cancer (n = 5726) Age-adjusted Multivariate III 㛳 Rectal cancer (n = 2188) Age-adjusted Multivariate III 㛳

P Value for BetweenStudies Heterogeneity†

P Value for BetweenStudies Heterogeneity Due to Sex†

1

2

3

4

5

P Value for Trend

1.00 1.00 1.00 1.00

0.90 (0.84-0.97) 0.91 (0.85-0.98) 0.92 (0.85-0.99) 0.93 (0.86-1.00)

0.86 (0.79-0.94) 0.88 (0.82-0.95) 0.90 (0.83-0.97) 0.91 (0.84-0.98)

0.90 (0.84-0.97) 0.93 (0.87-1.00) 0.96 (0.88-1.04) 0.97 (0.90-1.05)

0.84 (0.77-0.92) 0.88 (0.82-0.95) 0.92 (0.84-1.01) 0.94 (0.86-1.03)

.002 .01 .38 .75

.14 .38 .31 .45

.66 .92 .98 .74

1.00 1.00

0.91 (0.83-0.99) 0.94 (0.86-1.03)

0.86 (0.78-0.95) 0.92 (0.83-1.02)

0.91 (0.84-0.99) 1.00 (0.91-1.10)

0.87 (0.79-0.95) 1.00 (0.90-1.11)

.03 .40

.31 .70

.71 .83

1.00 1.00

0.91 (0.80-1.04) 0.93 (0.81-1.07)

0.86 (0.75-0.98) 0.89 (0.77-1.03)

0.89 (0.77-1.01) 0.93 (0.80-1.09)

0.81 (0.71-0.93) 0.85 (0.72-1.01)

.03 .18

.47 .52

.81 .66

P Value for Common Effects by Tumor Site†

.44 .07

*The quintiles were defined within each individual study using the subcohort for the 2 case-cohort studies (the Canadian National Breast Screening Study and the Netherlands Cohort Study) and the baseline cohort for the remaining studies. †For quintile 5. ‡Adjusted for age; body mass index (calculated as weight in kilograms divided by the square of height in meters) (⬍23, 23-⬍25, 25-⬍30, ⱖ30; height (men: ⬍1.70, 1.70-⬍1.75, 1.75-⬍1.80, 1.80-⬍1.85, ⱖ1.85 m; women: ⬍1.60, 1.60-⬍1.65, 1.65-⬍1.70, 1.70-⬍1.75, ⱖ1.75 m); education (⬍high school graduate, high school graduate,⬎high school graduate); physical activity (low, medium, high); family history of colorectal cancer (no, yes); use of postmenopausal hormone therapy (premenopausal, never, ever); oral contraceptive use (never, ever); use of nonsteroidal anti-inflammatory drugs (no, yes); multivitamin use (no, yes ⬍6 times/wk, yes ⱖ6 times/wk, yes missing dose for the Breast Cancer Detection Demonstration Project Follow-up Study, Health Professionals Follow-up Study, Iowa Women’s Health Study, Nurses’ Health Study [a and b], and Women’s Health Study; no, yes, for the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study, Cancer Prevention Study II Nutrition Cohort, Netherlands Cohort Study, and New York State Cohort); smoking habits (never, past [⬍20 y, 20-⬍40 y, ⱖ40 y], current [⬍25 cigarettes/d and ⬍40 y, ⬍25 cigarettes/d and ⱖ40 y, ⱖ25 cigarettes/d and ⬍40 y, ⱖ25 cigarettes/d and ⱖ40 y]); and total energy (continuous). §Multivariate I ⫹ intake of dietary folate (quintiles). 㛳Multivariate II ⫹ intake of red meat (quintiles), total milk (quartiles), and alcohol (0, ⬎0-⬍5, 5-⬍15, 15-⬍30, ⱖ30 g/d).

Figure 1. Study-Specific and Pooled Multivariate Relative Risks (RRs) of Colorectal Cancer Comparing the Highest vs the Lowest Quintile of Dietary Fiber Intake Source NHSa WHS ATBC CPS2-w NLCS-w HPFS BCDDP NHSb NYSC-w CPS2-m NYUWHS IWHS CNBSS SMC NLCS-m NYSC-m ORDET Pooled RR (95% CI)

0.94 (0.86-1.03)

0.2

0.5

1.0

2.0

7.0

RR (95% Confidence Interval)

The squares and horizontal lines correspond with the multivariate study-specific relative risks (RRs) and 95% confidence intervals (CIs), for the highest quintile of dietary fiber intake compared with the lowest. The relative risks were adjusted for the covariates listed in multivariate model III in Table 2. The size of a square reflects the study-specific weight (inverse of the variance), and the diamond represents the pooled relative risk and 95% confidence interval. The vertical dashed line represents the pooled relative risk. The abbreviations of the studies are listed in Table 1. 2852 JAMA, December 14, 2005—Vol 294, No. 22 (Reprinted)

in women). The association between dietary fiber intake and risk of colorectal cancer was not significantly modified by sex or age at diagnosis; compared with the lowest quintile the pooled multivariate RR for the highest quintile was 0.96 (95% CI, 0.82-1.13) for men; 0.93 (95% CI, 0.83-1.04) for women; (P for between-studies heterogeneity due to sex=.74); 0.96 (95% CI, 0.82-1.12) for cases diagnosed in patients younger than age 65 years (3048 cases); and 0.92 (95% CI, 0.79-1.06) for patients diagnosed at age 65 years and older (5033 cases). We also found no statistically significant differences in the association between dietary fiber intake and colorectal cancer risk by body mass index (calculated as weight in kilograms divided by the square of height in meters), smoking, alcohol consumption, and red meat intake (data not shown). In addition, the results were similar in European and North American studies: the pooled multivariate RR in the highest quintile vs the lowest was 0.99 (95% CI, 0.80-1.23) for the European studies and 0.92 (95% CI, 0.83-




1.02) for the North American studies (P for difference= .45). To examine whether the association between dietary fiber intake and risk of colorectal cancer was modified by length of follow-up, we performed separate analyses for cases diagnosed within the first 5 years of follow-up and for cases diagnosed at least 5 years after their baseline assessment. When follow-up time was limited to only the first 5 years, there was a suggestion of an inverse association (pooled multivariate RR = 0.87; 95% CI, 0.76-1.00 in the highest quintile vs the lowest; 3257 cases). However, after a 5-year latency period between the baseline diet assessment and outcome ascertainment, no association was observed (pooled multivariate RR = 1.00; 95% CI, 0.891.12 in the highest quintile vs the lowest; 4824 cases). In categorical analyses using identical absolute intake cut points across

studies, the pooled age-adjusted RR was 0.90 (95% CI, 0.75-1.08) and the pooled multivariate RR was 1.00 (95% CI, 0.851.17) (TABLE 3) for comparisons of dietary fiber intake of 30 or more g/d vs 10 to less than 15 g/d. However, the pooled multivariate RR was significantly elevated (RR=1.18; 95% CI, 1.051.31) among individuals with dietary fiber intake less than 10 g/d (11% of the overall study population) compared with 10 to less than 15 g/d. Because the association between dietary fiber intake and risk of colorectal cancer was nonlinear, we calculated measurement error corrected RRs for comparisons of less than 10 g/d vs 10 or more g/d. For this comparison, the strongest confounder was smoking status. Among the studies that had colorectal cancer cases with dietary fiber intake of less than 10 g/d, measured smoking status, and had a sufficient range of dietary fiber intake in their validation study to perform the mis-

classification analysis, correction for misclassification of dietary fiber intake strengthened the association: the pooled age and smoking adjusted RR comparing less than 10 g/d vs 10 or more g/d of dietary fiber intake changed from 1.22 (95% CI, 1.10-1.35) to 2.16 (95% CI, 1.12-4.16) after correction for measurement error. The nonparametric regression curve obtained after combining all studies into a single data set showed a pattern similar to the categorical analyses in which study-specific RRs were pooled (FIGURE 2): the multivariate RR declined with increasing dietary fiber intake up to about 15 g/d, but then flattened out (P for nonlinearity=.05). There was a suggestion that the association with dietary fiber intake differed by tumor site (P for common effects by tumor site for the highest quintile=.07) (Table 2). Comparing the highest vs lowest quintile of intake, a

Table 3. Pooled Relative Risks of Colorectal Cancer for Categories of Dietary Fiber Intake

Dietary Fiber Intake, g/d ⬍10 Colorectal cancer† No. of cases Person-years

10-⬍15

15-⬍20

20-⬍25

25-⬍30

ⱖ30

609

1681

2263

1740

1001

785

513 317

1 591 322

1 870 758

1 183 334

514 142

313 572

P Value P Value for for BetweenP Value BetweenStudies for Studies Heterogeneity Trend Heterogeneity* Due to Sex*

Age-adjusted

1.27 (1.15-1.40)

1.00

0.99 (0.93-1.06) 0.95 (0.87-1.03) 0.90 (0.80-1.01) 0.90 (0.75-1.08)

.18

.15

.05

Multivariate‡

1.18 (1.05-1.31)

1.00

1.02 (0.95-1.10) 1.01 (0.92-1.10) 0.99 (0.87-1.12) 1.00 (0.85-1.17)

.68

.54

.22

Colon cancer† No. of cases

430

1203

1620

1223

711

537

Person-years

513 311

1 591 290

1 870 713

1 183 264

514 073

313 513

Age-adjusted

1.24 (1.11-1.40)

1.00

1.00 (0.92-1.08) 0.94 (0.85-1.04) 0.94 (0.83-1.07) 0.90 (0.73-1.12)

.44

.18

.02

Multivariate‡

1.17 (1.03-1.34)

1.00

1.04 (0.95-1.13) 1.03 (0.93-1.15) 1.08 (0.93-1.25) 1.04 (0.86-1.26)

.17

.83

.10

⬍10

10-⬍15

Rectal cancer§

15-⬍20

20-⬍25

ⱖ25

No. of cases

159

427

576

452

417

Person-years

505 039

1 589 654

1 853 445

1 141 533

672 692

Age-adjusted

1.35 (1.11-1.64)

1.00

0.98 (0.84-1.14) 0.96 (0.78-1.18) 0.85 (0.70-1.04)

.17

.77

.58

Multivariate‡

1.18 (0.82-1.68)

1.00

1.00 (0.86-1.17) 0.96 (0.80-1.15) 0.87 (0.68-1.09)

.27

.67

.77

*For the highest category. †For the colorectal and colon cancer analyses, the Netherlands Cohort Study and the New York State Cohort were excluded from the ⬍10 g/d category because these studies did not have any cases in that category; ORDET was excluded from the ⱖ30 g/d category because this study did not have any cases in that category. ‡Adjusted for age; body mass index (calculated as weight in kilograms divided by the square of height in meters) (⬍23, 23-⬍25, 25-⬍30, ⱖ30; height (men: ⬍1.70, 1.70-⬍1.75, 1.75⬍1.80, 1.80-⬍1.85, ⱖ1.85 m; women: ⬍1.60, 1.60-⬍1.65, 1.65-⬍1.70, 1.70-⬍1.75, ⱖ1.75 m); education (⬍high school graduate, high school graduate, ⬎high school graduate); physical activity (low, medium, high); family history of colorectal cancer (no, yes); use of postmenopausal hormone therapy (premenopausal, never, ever); oral contraceptive use (never, ever); use of nonsteroidal anti-inflammatory drugs (no, yes); multivitamin use (no, yes ⬍6 times/wk, yes ⱖ6 times/wk, yes missing dose for the Breast Cancer Detection Demonstration Project Follow-up Study, Health Professionals Follow-up Study, Iowa Women’s Health Study, Nurses’ Health Study [a and b], and Women’s Health Study; no, yes, for the AlphaTocopherol Beta-Carotene Cancer Prevention Study, Cancer Prevention Study II Nutrition Cohort, Netherlands Cohort Study, and New York State Cohort); smoking habits (never, past [⬍20y, 20-⬍40y, ⱖ40 y], current [⬍25 cigarettes/d and ⬍40 y, ⬍25 cigarettes/d and ⱖ40 y, ⱖ25 cigarettes/d and ⬍40 y, ⱖ25 cigarettes/d and ⱖ40 y]; alcohol (0 g/d, ⬎0-⬍5 g/d, 5-⬍15 g/d, 15-⬍30 g/d, ⱖ30 g/d); dietary intake of folate (quintiles), red meat (quintiles), total milk (quartiles), and total energy (continuous). §For the rectal cancer analyses, the highest category of dietary fiber intake is defined as ⱖ25 g/d due to small numbers of cases with higher intakes. For the rectal cancer analyses, the Netherlands Cohort Study, New York State Cohort, and ORDET were excluded from the ⬍10 g/d category because these studies did not have any cases in that category; the Cancer Prevention Study II Nutrition Cohort was excluded from the ⱖ25 g/d category because this study did not have any cases in that category; and the male cohort of the New York State Cohort was excluded from the rectal cancer analyses because this study had no cases in the reference group.




2853


null association was found for colon cancer (pooled multivariate RR = 1.00; 95% CI, 0.90-1.11), whereas a borderline-significant, weak inverse association was found for rectal cancer (pooled multivariate RR = 0.85; 95% CI, 0.721.01). Further analyses of proximal colon cancer (pooled multivariate RR=1.05; 95% CI, 0.91-1.21) and distal colon cancer separately (pooled multivariate RR=0.96; 95% CI, 0.80-1.14) showed no statistically significant association (P for common effects by tumor site for the highest quintile = .24). In analyses of the sources of dietary fiber, fiber intakes from cereals and fruits were each associated with apFigure 2. Nonparametric Regression Curve for the Association Between Dietary Fiber Intake and Risk of Colorectal Cancer

Multivariate Relative Risk

2.0 1.0 0.5 Regression Curve 95% Confidence Interval 0.1 0

10

20

30

40

Total Dietary Fiber Intake, g/d

50

proximately a 10% reduction in risk of colorectal cancer in the age-adjusted model comparing the highest quintile with the lowest (TABLE 4). However, after adjustment for potential colorectal cancer risk factors, the associations were attenuated and not statistically significant (pooled multivariate RR = 1.00; 95% CI, 0.93-1.08 for fiber from cereals; pooled multivariate RR=0.96; 95% CI, 0.89-1.04 for fiber from fruits in the highest quintile vs the lowest). Dietary fiber from vegetables was not associated with risk of colorectal cancer in both the age-adjusted and multivariate models. When associations with specific sources of dietary fiber were examined by tumor site, we found that the associations with fiber intake from cereals were significantly different between colon and rectal cancer (P for common effect by tumor site for the highest quintile=.05), even though neither association was statistically significant. Comparing the highest vs the lowest quintile for fiber intake from cereals, the pooled multivariate RR was 0.91 (95% CI, 0.78-1.06, P for trend = .20) for rectal cancer, and 1.03 (95% CI, 0.94-1.13, P for trend=.90) for colon cancer. For fiber intake from fruits and from vegetables, no signifi-

cant differences by tumor site were observed (data not shown). Intakes of whole grain and refined grain food were each not statistically associated with risk of colorectal cancer: the pooled multivariate RR in the highest quintile vs the lowest were 0.92 (95% CI, 0.84-1.00, P for trend=.21) for whole grain food and 1.01 (95% CI, 0.91-1.13, P for trend = .94) for refined grain food. Although the results did not significantly differ by tumor site for both whole and refined grain food intake, there was a suggestion that whole grain food intake was inversely associated with risk of rectal cancer (pooled multivariate RR=0.81; 95% CI, 0.65-1.00 in the highest quintile vs the lowest, P for trend=.07). In the analyses of grain foods, if dietary folate intake was not included as a covariate, the results did not change. COMMENT In this pooled analysis of 13 prospective cohort studies, we observed a statistically significant inverse association between dietary fiber intake and risk of colorectal cancer in the ageadjusted model. However, the overall association was attenuated and no longer statistically significant after ad-

Table 4. Pooled Relative Risks of Colorectal Cancer by Sources of Dietary Fiber Intake

Quintile* Fiber Source Cereals Age-adjusted Multivariate‡ Fruits Age-adjusted Multivariate‡ Vegetables Age-adjusted Multivariate‡

P Value for BetweenStudies Heterogeneity†

P Value for BetweenStudies Heterogeneity Due to Sex†

1

2

3

4

5

P Value for Trend

1.00 1.00

0.94 (0.87-1.02) 0.97 (0.90-1.05)

0.94 (0.87-1.01) 1.00 (0.93-1.08)

0.93 (0.86-1.00) 1.01 (0.94-1.09)

0.90 (0.83-0.97) 1.00 (0.93-1.08)

.001 .57

.20 .71

.23 .53

1.00 1.00

0.96 (0.90-1.03) 0.99 (0.92-1.07)

0.90 (0.84-0.97) 0.95 (0.88-1.02

0.90 (0.83-0.96) 0.96 (0.89-1.03)

0.88 (0.81-0.96) 0.96 (0.89-1.04)

.004 .30

.23 .75

.55 .15

1.00 1.00

0.97 (0.88-1.06) 0.98 (0.90-1.07)

0.92 (0.84-1.00) 0.95 (0.87-1.02)

0.91 (0.84-0.99) 0.95 (0.87-1.03)

0.97 (0.90-1.05) 1.02 (0.94-1.11)

.39 .58

.24 .71

.66 .75

*The quintiles were defined within each individual study using the subcohort for the 2 case-cohort studies (the Canadian National Breast Screening Study and the Netherlands Cohort Study) and the baseline cohort for the remaining studies. †For highest quintile. ‡Adjusted for age; body mass index (calculated as weight in kilograms divided by the square of height in meters) (⬍23, 23-⬍25, 25-⬍30, ⱖ30; height (men: ⬍1.70, 1.70-⬍1.75, 1.75⬍1.80, 1.80-⬍1.85, ⱖ1.85 m; women: ⬍1.60, 1.60-⬍1.65, 1.65-⬍1.70, 1.70-⬍1.75, ⱖ1.75 m); education (⬍high school graduate, high school graduate,⬎high school graduate); physical activity (low, medium, high); family history of colorectal cancer (no, yes); use of postmenopausal hormone therapy (premenopausal, never, ever); oral contraceptive use (never, ever); use of nonsteroidal anti-inflammatory drugs (no, yes); and multivitamin use (no, yes ⬍6 times/wk, yes ⱖ6 times/wk, yes missing dose for the Breast Cancer Detection Demonstration Project Follow-up Study, Health Professionals Follow-up Study, Iowa Women’s Health Study, Nurses’ Health Study [a and b], and Women’s Health Study) no, yes, for the Alpha-Tocopherol Beta Carotene Cancer Prevention Study, Cancer Prevention Study II Nutrition Cohort, Netherlands Cohort Study, and New York State Cohort); smoking habits (never, past [⬍20 y, 20-⬍40 y, ⱖ40 y], current [⬍25 cigarettes/d and ⬍40 y, ⬍25 cigarettes/d and ⱖ40 y, ⱖ25 cigarettes/d and ⬍40 y, ⱖ25 cigarettes/d and ⱖ40 y]); alcohol (0 g/d, ⬎0-⬍5 g/d, 5-⬍15 g/d, 15-⬍30 g/d, ⱖ30 g/d); dietary intake of folate (quintiles), red meat (quintiles), total milk (quartiles), and total energy (continuous).





justing for other colorectal cancer risk factors. When intakes of dietary fiber were examined separately by specific food sources, none were associated with risk of colorectal cancer. However, there was a suggestion that intake of dietary fiber from cereals and intake of dietary fiber from whole grain foods were both associated with a weak reduction in risk of rectal cancer. The association between dietary fiber intake and risk of colorectal cancer has been inconsistent among observational studies and several factors may explain the disparity: potential biases in each study, the failure to adjust for covariates in the multivariate models, and the range of dietary fiber intake. Inconsistent results also have been reported from randomized clinical trials of dietary fiber supplementation on the recurrence of colorectal adenomas (precursors of colorectal cancer); most trials have found no reduced risk of adenoma recurrence with dietary fiber supplementation compared with placebo,9-12 but one trial found a significantly increased risk of adenoma recurrence in the psyllium supplementation group.48 A statistically significant reduction in risk of colorectal cancer with higher dietary fiber intake has been observed in most case-control studies.49 However, case-control studies are prone to recall bias because dietary assessments are obtained after cancer diagnosis and also are prone to selection bias because control participants who participate are likely to be particularly healthconscious. In addition, publication bias may contribute to the accumulation of literature with significant findings. On the other hand, the Pooling Project is less susceptible to these biases because diet was assessed prior to diagnosis and the studies were not required to have published on the association between dietary fiber intake and risk of colorectal cancer. The etiology of colorectal cancer has been studied extensively during the past few decades leading to the identification of many risk factors for colorectal cancer. Because earlier case-control

studies did not adjust for recently identified colorectal cancer risk factors, reported associations with dietary fiber may have been confounded by factors for which no adjustment was made in the multivariate models. The different results observed among recent studies also may be explained, in part, by the selection of the covariates that were included in the multivariate models. Recently the EPIC study, a multicenter prospective cohort study with 10 European countries (n = 519 978; 1721 cases), found a statistically significant 30% lower risk of colorectal cancer in the multivariate model adjusted for age, sex, weight, height, nonfat energy, energy from fat, and center (RR = 0.70; 95% CI, 0.58-0.85 in the highest quintile vs the lowest).13 Additional adjustment for folate intake did not change the result (RR = 0.68; 95% CI, 0.550.84), but noticeable attenuation was observed (RR = 0.79; 95% CI, 0.630.99) after adjusting for other risk factors such as education, physical activity, alcohol, smoking, and red meat intake. In the Pooling Project, the inverse association observed between dietary fiber intake and risk of colorectal cancer in the age-adjusted model (RR=0.84; 95% CI, 0.77-0.92) (Table 2) was attenuated after adjusting for age, nondietary risk factors, multivitamin use, and energy intake, but remained statistically significant (pooled multivariate RR = 0.88; 95% CI, 0.82-0.95) (Table 2, multivariate model I). However, further attenuation occurred after adjusting for dietary folate intake (pooled multivariate RR=0.92; 95% CI, 0.84-1.01) (Table 2, multivariate model II), but no observable attenuation was observed after adjusting for other dietary factors such as consumption of red meat, total milk, and alcohol intake (pooled multivariate RR=0.94; 95% CI, 0.86-1.03) (Table 2, multivariate model III). In our study, intake of folate was positively correlated with intake of dietary fiber, while intakes of red meat and total milk were inversely correlated with intake of dietary fiber, but the strength of correlations varied across studies. Intake of alcohol was posi-


tively correlated with intake of dietary fiber in some studies, but showed an inverse correlation in other studies. Because the degree of confounding by other risk factors of colorectal cancer may vary depending on characteristics of a study population, thorough examination for selection of covariates to be included in a multivariate model is needed. The range of dietary fiber intake reported within a study may be another factor that has contributed to different findings among studies. If the range of intake of a nutrient in a study is very narrow, a null association may be more likely observed. However, lack of variation in dietary fiber intake is unlikely to have accounted for the null association we found. In our analyses, the study-specific mean energy-adjusted dietary fiber intake was 9 to 20 g/d for men and 8 to 17 g/d for women in the lowest quintile and 23 to 41 g/d for men and 20 to 35 g/d for women in the highest quintile with a 1.8- to 3.0-fold difference in intakes between the 2 extreme quintiles across studies. This range is similar to the range observed in EPIC, which reported a statistically significant inverse association with dietary fiber intake. Mean dietary fiber intake in EPIC was 18 g/d for men and 16 g/d for women in the lowest quintile and 30 g/d for men and 24 g/d for women in the highest quintile (a 1.5to 1.7-fold difference).13 In addition, when we used identical absolute intake cut points across studies, no association was observed for dietary fiber intake of at least 30 g/d vs 10 to less than 15 g/d, which is similar to the quintile definitions used in EPIC. Because the Pooling Project is a retrospectively planned pooled analysis of the primary data, the food frequency questionnaires that were used to assess diet varied across studies. To take into account potential misclassification in dietary fiber intake that may arise from measurement error in energy intake, we calculated energy-adjusted intakes for each study. We also conducted analyses by categorizing dietary fiber intake using study-specific quin-



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tiles and identical absolute intake cut points across studies. In the studyspecific quintile analyses, true differences in population intakes were not taken into account, potentially resulting in misclassification of dietary fiber intake in the pooled results. However, misclassification could also have occurred in the analyses based on identical absolute intake cut points because dietary fiber intakes may vary across studies due to differences in the accuracy in which the food frequency questionnaires estimated dietary fiber. Despite the different potential for misclassification between these 2 analytic approaches, both showed no association between dietary fiber intake and risk of colorectal cancer above the lowest category of dietary intake. Several limitations of our analysis should be considered. Fiber intake is likely to be measured with error because of errors in how study participants estimate their consumption of fiber-containing foods and by errors in the food composition databases. A true association between dietary fiber intake and risk of colorectal cancer may be underestimated in our study. In addition, although we were able to correct for misclassification of dietary fiber intake at baseline, the single assessment of dietary fiber intake in our analysis may not reflect long-term usual intake as accurately as using repeated measurements of dietary intake during follow-up. However, use of repeated measurements of dietary fiber intake in the Nurses’ Health Study did not change substantially the risk estimates obtained from using baseline data only.50 Because dietary fiber intake was assessed only at baseline, we also could not examine the effects of dietary fiber intake during earlier life periods (eg, childhood or young adulthood) or lifelong fiber intake on risk of colorectal cancer. Although misclassification in fiber intake also may have occurred because we did not have information on the use of dietary fiber supplements, a recent US national survey found that the prevalence of nonvitamin/nonmineral supplement use, including fiber supplements, was less than

4%.51 Therefore, failure to measure use of fiber supplements is unlikely to have led to substantial misclassification of dietary fiber intake. A strength of the Pooling Project is that the individual data from each cohort were reanalyzed using a standard approach, which provided more flexibility in examining dose-response relationships, confounding, and effect modification than meta-analyses of the published literature, which frequently summarize risk estimates obtained for heterogeneous exposure categories with different adjustment for potential confounders. Also, we had high statistical power with over 8000 colorectal cancer cases, thus a substantial effect of fiber is unlikely to have been missed. In addition, in a subset of the studies we were able to correct for measurement error in dietary fiber intake using their validation study data. Our ability to correct for measurement error strengthened the estimated association observed between very low dietary fiber intake and colorectal cancer risk; however, it should be noted that in this analysis we could only adjust for age and smoking, the 2 strongest confounders in the multivariate analysis when comparing less than 10 vs 10 g/d or more of dietary fiber intake. In conclusion, we did not find support for a linear inverse association between dietary fiber intake and risk of colorectal cancer in a pooled analysis of 13 prospective cohort studies. Although high dietary fiber intake may not have a major effect on the risk of colorectal cancer, a diet high in dietary fiber from whole plant foods can be advised because this has been related to lower risks of other chronic conditions such as heart disease and diabetes.52 Author Affiliations: Department of Nutrition (Drs Park, Giovannucci, Hunter, Willett, and Smith-Warner), Department of Epidemiology (Drs Buring, Colditz, Giovannucci, Hunter, Spiegelman, Willett, SmithWarner, and Zhang), Department of Biostatistics (Dr Spiegelman), Harvard School of Public Health, Boston, Mass; Division of Preventive Medicine (Drs Buring and Zhang) and Channing Laboratory (Drs Colditz, Fuchs, Giovannucci, Hunter, and Willett), Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass; Harvard Center for Cancer Prevention, Boston, Mass (Drs Coldtiz, Hunter, and Willett); Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, Mass (Dr Fuchs); Department of Surgery and Centre for Clinical


Research, Central Hospital, Va¨stera˚s, Sweden (Dr Bergkvist); Epidemiology Unit, National Cancer Institute, Milan, Italy (Drs Berrino and Krogh); Department of Epidemiology, Maastricht University, Maastricht, the Netherlands (Dr van den Brandt); Department of Social and Preventive Medicine, University at Buffalo, State University of New York, Buffalo (Drs Freudenheim and Graham); Department of Epidemiology, TNO Nutrition and Food Research Institute, Zeist, the Netherlands (Dr Goldbohm); Division of Epidemiology, School of Public Health, University of Minnesota, Minneapolis (Drs Harnack and Jacobs); Risk Factor Monitoring and Methods Branch, Applied Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, Md (Ms Hartman); Karmanos Cancer Institute/Department of Pathology, Wayne State University, Detroit, Mich (Dr Kato); Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Md (Drs Leitzmann and Schatzkin); Epidemiology and Surveillance Research, American Cancer Society, Atlanta, Ga (Dr McCullough); Department of Public Health Sciences, University of Toronto, Toronto, Ontario (Dr Miller); Department of Epidemiology and Health Promotion, National Public Health Institute, Helsinki, Finland (Dr Pietinen); Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY (Dr Rohan); Division of Nutritional Epidemiology, The National Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden (Dr Wolk); and Department of Environmental Medicine, New York University, New York (Dr Zeleniuch-Jacquotte). Dr Park is now with the Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Md. Author Contributions: Dr Smith-Warner had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Park, Spiegelman, van den Brandt, Giovannucci, Goldbohm, Graham, Krogh, Pietinen, Rohan, Willett, Smith-Warner. Acquisition of data: Berrino, van den Brandt, Buring, Colditz, Fuchs, Giovannucci, Goldbohm, Graham, Harnack, Hartman, Kato, Krogh, McCullough, Miller, Pietinen, Rohan, Schatzkin, Willett, Wolk, ZeleniuchJacquotte, Zhang, Smith-Warner. Analysis and interpretation of data: Park, Hunter, Spiegelman, Bergkvist, Freudenheim, Fuchs, Giovannucci, Goldbohm, Graham, Harnack, Hartman, Jacobs, Kato, Leitzmann, Willett, Wolk, Zhang, Smith-Warner. Drafting of the manuscript: Park, Fuchs, Graham. Critical revision of the manuscript for important intellectual content: Park, Hunter, Spiegelman, Bergkvist, Berrino, van den Brandt, Buring, Colditz, Freudenbheim, Fuchs, Giovannucci, Goldbohm, Graham, Harnack, Hartman, Jacobs, Kato, Krogh, Leitzmann, McCullough, Miller, Pietinen, Rohan, Schatzkin, Willett, Wolk, Zeleniuch-Jacquotte, Zhang, Smith-Warner. Statistical analysis: Park, Spiegelman, Fuchs, Graham, Harnack, Willett, Smith-Warner. Obtained funding: Spiegelman, Bergkvist, Berrino, van den Brandt, Fuchs, Giovannucci, Graham, Pietinen, Schatzkin, Willett, Wolk, Smith-Warner. Administrative, technical, or material support: Hunter, Colditz, Graham, Kato, McCullough, Pietinen, Willett, Wolk, Zhang. Study supervision: Spiegelman, Graham, Leitzmann, Smith-Warner. Financial Disclosures: None reported. Funding/Support; The study was funded by research grants CA55075 and CA78548 from the National Institutes of Health and by the National Colorectal Cancer Research Alliance. Role of the Sponsor: The sponsors were not involved



DIETARY FIBER AND COLORECTAL CANCER RISK in the study design, data analysis, interpretation of results, or writing of the report. Acknowledgment: We thank Ruifeng Li, MS, Christine Rivera, MS, and Shiaw-Shyuan Yaun, MS, Harvard School of Public Health, for their assistance with data management and statistical analyses.

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